Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Utilization of wireless pH monitoring technologies: a summary of the proceedings from the esophageal diagnostic working group.

Gastroesophageal reflux disease (GERD) can be difficult to diagnose - symptoms alone are often not enough, and thus, objective testing is often required. GERD is a manifestation of pathologic levels of reflux into the esophagus of acidic, nonacidic, and/or bilious gastric content. However, in our current evidence-based knowledge approach, we only have reasonable outcome data in regards to acid reflux, as this particular type of refluxate predictably causes symptoms and mucosal damage, which improves with medical or surgical therapy. While there are data suggesting that nonacid reflux may be responsible for ongoing symptoms despite acid suppression in some patients, outcome data about this issue are limited. Therefore, this working group believes that it is essential to confirm the presence of acid reflux in patients with 'refractory' GERD symptoms or extraesophageal symptoms thought to be caused by gastroesophageal reflux before an escalation of antireflux therapy is considered. If patients do not have pathologic acid reflux off antisecretory therapy, they are unlikely to have clinically significant nonacid or bile reflux. Patients who do not have pathologic acid gastroesophageal reflux parameters on ambulatory pH monitoring then: (i) could attempt to discontinue antisecretory medications like proton pump inhibitors and H2-receptor antagonists (which are expensive and which carry risks - i.e. C. diff, etc.); (ii) may undergo further evaluation for other causes of their esophageal symptoms (e.g. functional heartburn or chest pain, eosinophilic esophagitis, gastroparesis, achalasia, other esophageal motor disorders); and (iii) can be referred to an ear, nose, and throat/pulmonary/allergy physician for assessment of non-GERD causes of their extraesophageal symptoms.

A priori expectancy bias in patients with panic disorder.

BACKGROUND: Several studies have indicated that phobic participants tend to overassociate fear-relevant stimuli and aversive outcomes, i.e, they show a covariation bias. Such a bias seems to be a powerful way to confirm danger expectations and enhance fear. Therefore, a covariation bias might be an important factor in the maintenance of fear. METHODS: To investigate a covariation bias in patients with panic disorder, we had 29 patients and 29 healthy control participants rate the a priori probabilities with which they would expect pictures of mushrooms, spiders, erotic scenes, and emergency situations to be paired with a tone, shock, or nothing. RESULTS: This is the first study to show that patients with panic disorder specifically overestimate the association between panic-relevant stimuli and a following negative consequence. This distorted contingency expectancy represents a panic-specific covariation bias, since it was not observable for other stimuli-consequence combinations and only to a significantly lesser degree in control participants. CONCLUSIONS: The underpinning hypothesis is that overestimation of threat plays a casual role in the origins and maintenance of anxiety. Thus anxiety may induce a covariation bias, which in turn may enhance the perceived threat, which in turn may intensify the anxiety etc. This reciprocal relationship between covariation bias and anxiety may have clinical implications for prediction and treatment in patients with panic disorder.

A priori expectancy bias and its relation to shock experience and anxiety: a naturalistic study in patients with an automatic implantable cardioverter defibrillator.

Patients with an automatic implantable cardioverter defibrillator (AICD) may offer an unique naturalistic opportunity to study whether expectancy biases develop because of precipitating aversive or traumatic experiences and/or because of elevated anxiety. An expectancy bias and its associations with AICD discharge and anxiety was examined in 24 AICD patients with a thought experiment. While patients without AICD discharge exhibited no expectancy bias, patients with discharge experiences were found to expect that stimuli depicting medical emergency situations will be followed by an aversive consequence. The magnitude of their expectancy bias was positively correlated with their anxiety level. In the group with AICD discharge, patients with low anxiety levels exhibited no bias, while patients with high anxiety levels exhibited a rather strong bias. It seems that the experience of an aversive or traumatic event, here an AICD discharge, is a necessary (but not sufficient) precipitating event for the development of an expectancy bias. If such an event happens, trait anxiety level presumably determines if and how strong the expectancy bias will be.

No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone.

In a recent study we demonstrated that recombinant human growth hormone (r-hGH; Saizen) delayed tumor-induced cachexia in human tumor xenografts in vivo. Such a therapeutic effect could have a great impact in the supportive care of advanced cancer patients. Before large clinical studies are initiated possible growth stimulation should be excluded. This question was investigated in vitro in 20 human tumor models, which had been established in serial passage in nude mice. The effect of continuous exposure of r-hGH was investigated at dose levels ranging from 0.3 ng/ml up to 0.1 microg/ml in colorectal (n=2), gastric (n=1), non-small cell lung (n=4), small cell lung (n=1), mammary (n=3), ovarian (n=2), prostate (n=2) and renal cancers (n=2), and melanoma (n=3) using a modified Hamburger and Salmon clonogenic assay. The results show that there was neither tumor growth inhibition nor any evidence for tumor growth stimulation in any of the tumors studies. Therefore this preclinical study in 20 human tumor models indicated no direct risk for tumor growth enhancement.

[Self-reported substance abuse related emergencies: frequency and nature]. / Drogennotfälle: Häufigkeit und Umstände aus der Sicht der Betroffenen.

OBJECTIVE: The aim of this study was to estimate the frequency and nature of self-reported and drug-related emergencies. METHODS: 47 patients of a ward for opiate detoxification were interviewed about their experiences with drug-related emergencies. Typical categories had to be found like overdoses, seizures, accidents and suicide attempts respectively. RESULTS: 68% had own experience with drug-related emergency. A majority suffered opiate overdose with different extensions as unconsciousness or breath-depression. Alcohol and polydrug use was associated with overdose. Drug-related accidents were only reported by men. Half the number of drug-related emergencies were treated in hospital. Most emergencies occurred alone either in a home environment or outside. CONCLUSION: Harm reduction interventions like observed user rooms should be established. Furthermore other strategies to reduce the number of emergencies as sharing naloxon or resuscitation programs in wards for detoxification could also be an effective method to prevent near fatal or fatal overdoses in dependent subjects.

Anxiety in patients with an automatic implantable cardioverter defibrillator: what differentiates them from panic patients?

OBJECTIVE: Anxiety seems to be a frequent problem in patients with an automatic implantable cardioverter defibrillator (AICD). Distressing experiences before or after AICD implantation such as resuscitation, or AICD shocks are suspected as causes for enhanced anxiety levels. A closer examination of the level and structure of anxiety in AICD patients and a comparison with panic patients might help to examine additionally both conditioning and cognitive models of anxiety. METHODS: There were 61 AICD patients examined with a specifically designed AICD questionnaire and standardized anxiety and depression questionnaires. Subgroups of AICD patients without, with some, and with definite anxiety related to AICD shocks were compared with panic patients and healthy control subjects. RESULTS: Although fear of dying was greatly reduced by AICD implantation, approximately one third of the AICD patients, especially patients with definite anxiety related to AICD shocks, were characterized both by enhanced anxiety levels and avoidance behavior. These patients were comparable with panic patients in most questionnaire scores. Anxiety levels were not associated with objective AICD shock experiences or medical variables. CONCLUSIONS: Anxiety in AICD patients seems to be unrelated to traumatic experiences, a finding that casts doubt on pure conditioning models of anxiety. Presumably, a life-threatening cardiac disorder increases the likelihood for catastrophic interpretations of bodily signs, especially in anxiety prone AICD patients. In accordance with cognitive models of panic disorder, this cognitive dysfunction could lead to anxiety and depression levels comparable with those of panic patients.

Frontal brain asymmetry as a biological substrate of emotions in patients with panic disorders.

BACKGROUND: Right frontal hemisphere activation, as indicated by reduced frontal alpha amplitude, seems to represent activation of an avoidance-withdrawal system and seems to be associated with negative emotions. Since patients with panic disorder are characterized by both negative emotions and avoidance-withdrawal behavior, we expected them to show greater right than left frontal hemisphere activation. METHODS: Spontaneous electroencephalography was recorded from the left and right frontal and parietal scalp regions of 23 patients with panic disorder patients without a diagnosis of depression and from 25 healthy control participants during the following conditions: rest, confrontation with neutral, panic-relevant, anxiety-relevant but panic-irrelevant, or anxiety-irrelevant but emotionally relevant stimuli, and performance of a motor task. Their emotional state during these conditions was assessed by the Self-Assessment Manikin. RESULTS: In patients with panic disorders, there were asymmetries in frontal hemisphere activation during resting phases and when confronted with anxiety-relevant stimuli. Their right frontal alpha power was significantly decreased compared with the left, while control participants did not show frontal brain asymmetry during these phases. There was no frontal brain asymmetry when patients observed an emotionally neutral picture or performed a motor task. Under these conditions, left and right frontal hemisphere alpha activation of patients with panic disorder and healthy participants were comparable. CONCLUSIONS: These data support the hypothesis that patients with panic disorder are characterized by greater activation of a right frontal avoidance-withdrawal system in negatively valenced situations. The findings are interpreted as biological evidence for a disturbed cortical processing in patients with panic disorder.

Associations between cortical slow potentials and clinical rating scales in panic disorder: a 1.5-year follow-up study.

In a previous study of 15 panic patients, we demonstrated that body-related (somatic) word stimuli elicited an enhanced positive cortical slow wave compared to non-somatic word stimuli. Healthy controls did not show this difference. The present paper reports on psychometric ratings in relation to cortical slow waves in these patients. Patients were clinically reexamined after about 1.5 years. Although no significant correlations between neurophysiology and psychometric measures could be found at the onset of the study, there was a significant correlation between improvement over the follow-up period and neurophysiology. A decline in the Hamilton Anxiety Scale (HAMA), which proved to be the best estimate for improvement, was associated with the relative magnitude of the positive slow wave elicited by somatic stimuli. Our findings support cognitive models of panic disorder, which stress that abnormal processing of bodily symptoms is relevant for the development and/or maintenance of the disorder.

Decreased duration and altered topography of electroencephalographic microstates in patients with panic disorder.

The topography and temporal sequence of scalp electrical fields were analyzed by adaptive segmentation of the continuous electroencephalogram (EEG) in 27 patients with panic disorder and 28 control subjects during rest phases and during the viewing of a neutral (mushroom) or an emotionally relevant (casualty) picture. The results indicate decreased duration of brain microstates in panic patients during all conditions. Comparison of the resting phases with the viewing conditions revealed a significant acceleration of EEG microstates in both the patients and the control subjects. Patients and control subjects differed in the topography of the fields during rest: control subjects showed a left-anterior/right-posterior orientation, while panic patients showed a predominantly right-anterior/left-posterior orientation. Neither group displayed any topographic changes when viewing the mushroom picture. However, when viewing the anxiety-specific casualty picture, panic patients shifted fields in a different way than did control subjects. Centroid topography does not permit clear localization of the cortical generators. It is concluded that panic patients show a generally increased cortical activation compared with healthy control subjects, and activate different neuronal arrays when viewing an anxiety-specific stimulus.

Behavioral and neurophysiological evidence for altered processing of anxiety-related words in panic disorder.

Body-related and nonsomatic words were presented tachistoscopically to 15 panic patients and 15 healthy controls at each participant's threshold for correctly identifying 50% of neutral words. Behavioral (proportion of words correctly recognized) and electrocortical (event-related brain potentials [ERPs]) measures were registered. Panic patients recognized more body-related than nonsomatic words, and body-related as compared with nonsomatic words elicited, in these patients, significantly larger P300 amplitudes and enhanced positive slow waves (600 to 800 ms after stimulus presentation). In healthy controls, the number of correct recognized words and the ERPs were not differentially affected by the 2 word types. These results are grossly consistent with cognitive models of panic disorders, assuming that certain bodily sensation are perceived and processed in an affective manner that differentiates panic patients from healthy controls.

Intra-tumoral application of a heregulin-exotoxin-a fusion protein causes rapid tumor regression without adverse systemic or local effects.

Tumor toxins are recombinant, bifunctional proteins which comprise a tumor-cell-specific recognition domain and an enzymatic toxin domain. We have evaluated the in vivo effects of a tumor toxin that specifically recognizes the erbB-3 and erbB-4 receptors (HRG beta 1-ETA). High doses of HRG beta 1-ETA administered systemically (intracardially or intraperitoneally) caused acute liver necrosis and were lethal. The same dose of tumor toxins applied subcutaneously had no detectable histopathological effects. The anti-tumor activity of HRG beta 1-ETA was tested in nude mice with xenografts of a human breast tumor, MAXF1162. The MAXF1162 tumor grew rapidly upon s.c. implantation. Intra-tumoral application of HRG beta 1-ETA (7 times 5 micrograms over a period of 21 days) induced complete regression of tumors. At the time the treatment was terminated, no tumor cells were detectable microscopically. Evaluation of the liver of treated animals revealed no significant toxicity in the effective dose range. These experiments indicate that tumor toxins can become valuable for local tumor treatment and for reduction of tumor burden.

Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells.

We have selected a panel of human tumor xenografts for in vitro and in vivo studies that allows an indication of selectivity of action of novel chemotherapeutic agents. We report here the antitumor activity of the flavone flavopiridol (previously designated L86-8275), which has been selected for further studies based in part on its behavior in the anticancer drug screening system of the United States National Cancer Institute. Eighteen human tumor and five cell line-derived xenografts established by serial passage in nude mice in our laboratory were used as tumor models for in vitro investigations using a modified double-layer soft agar assay. In vivo investigations were completed in nude mice bearing advanced-stage s.c. growing prostate cancer xenografts. Antitumor activity in vitro (test/control

Processing of tumor tissues for vaccination with autologous tumor cells.

Vaccination with gene-transfected tumor cells has recently been proposed as a new strategy in the immunotherapy of cancer. Since autologous tumor cells provide an optimal antigen profile, the possibility of generating single cell suspensions from renal cell carcinoma (RCC), malignant melanoma (MM), colon carcinoma (CC), and non-small-cell lung cancer (NSCLC) biopsies was investigated. One hundred and seventy-four tumor biopsies were processed by mechanic and enzymatic dissociation, yielding 1-2 x 10(6) cells/g tumor (median), irrespective of tumor type. Primary tumor cell cultures (PTCC) of > or = 10(7) cells were established from 29 of 86 (34%) RCC, 14 of 38 (37%) MM, 11 of 23 (48%) NSCLC and 4 of 27 (15%) CC specimens. The amount of non-tumor cells, as assessed by morphology and immunocytology, was generally low (< 30%) in RCC (35 of 41) and MM (11 of 17), while it exceeded 60% in 8 of 11 PTCC from NSCLC and 3 of 11 CC. A high tumor cell yield was obtained in biopsies with a high degree of vascularization and in the virtual absence of necrosis. Thus, PTCC > or = 10(7) cells were obtained in 73% of MM with a high degree of vascularization and in 22% of MM with a low degree of vascularization (p < 0.007). Long-term tumor cell cultures exceeding 20 passages were established in 24 of 86 (18%) RCC, 7 of 38 (18%) MM and 3 of 27 (11%) CC, while successful implantation in nude mice was achieved in 8 of 20 RCC and 5 of 10 MM. Thus, under the conditions described, > or = 10(7) primary tumor cells of high purity could be generated from about one third of RCC and MM biopsies, while the success rate increased to > 50 and > 70%, respectively, in samples with a high degree of vascularization generated by an optimized biopsy technique excluding necrotic parts.

Cytotoxicity of TGF alpha-PE40 and correlation to expression of epidermal growth factor receptor.

TGF alpha-PE40 is a chimeric protein composed of transforming growth factor alpha (TGF alpha) linked to a modified Pseudomonas exotoxin (PE40). We tested the in vitro cytotoxicity of TGF alpha-PE40 on 23 different solid human tumour xenografts established in nude mice and human bone marrow cells from healthy donors, utilising a modified clonogenic assay. In order to distinguish non-specific toxicity from the targeted effects of TGF alpha-PE40, epidermal growth factor receptor (EGFR) expression of the tumours studied was assessed by Northern blot, slot blot and immunohistochemistry. TGF alpha-PE40 demonstrated differential cytotoxicity on human tumour xenografts in the clonogenic assay. No toxicity on human bone marrow cells was observed. In vitro activity of TGF alpha-PE40 showed a significant correlation with the expression of EGF receptors as determined by immunohistochemistry and slot blot. Further studies will be performed in order to determine the in vivo activity of this compound in tumour-bearing nude mice.

Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a polypeptide with specific effects on endothelial cell growth and blood vessel permeability. Recent studies demonstrated a key role for VEGF in tumor neovascularization, which is a prerequisite for tumor proliferation and metastasis. MATERIALS AND METHODS: We studied the expression of VEGF mRNA in a panel of 65 different human tumor xenografts of various histologies using Northern and slot blot analyses. Analyis of vessel density was performed morphologically and after immunohistochemical staining of endothelial cells. RESULTS: High expression levels were observed in 22/65 tumors. In melanoma, colorectal, gastric, breast and lung cancers only single tumors showed strong expression signals, whereas 7/10 renal cell carcinoma (RCC) xenografts demonstrated high levels of VEGF mRNA. Vessel density analysis revealed a clear correlation of VEGF mRNA expression with vascularization in RCC (p = 0.0048). Patient survival time was compared for tumors showing high versus low expression values. The overall 5-year survival rate was significantly lower for patients with high expression of VEGF mRNA (p = 0.0306). CONCLUSIONS: These data support the hypothesis that tumor cells of various histologies secrete VEGF, which acts as a paracrine factor to induce endothelial cell proliferation and vessel formation and mediates tumor progression.

Development of a propidium iodide fluorescence assay for proliferation and cytotoxicity assays.

A propidium iodide fluorescence assay (PIA) was developed to characterize the in vitro growth of human tumor cell lines as well as to test the cytotoxic activity of standard compounds. Propidium iodide (PI) was used as a dye which penetrates only damaged cellular membranes. Intercalation complexes are formed by PI with double-stranded DNA which effect an amplification of the fluorescence. Incubation of the total cell population with PI and subsequent fluorescence detection allowed assessment of the number of non-vital cells (first measurement). After freezing the cells at -20 degrees C for 24 h PI had access to total DNA leading to total cell population counts (second measurement). The number of viable cells was calculated by the difference between these two measurements. In the proliferation and cytotoxicity assays 5 x 10(3) cells per well were plated in 96 multiwells and finally stained with 50 micrograms/ml PI in 25 microliters for 10 min. A correlation between the log of cell number and the log of fluorescence units could be demonstrated over a 2.5-3 log range (r = 0.97). The lower limit of cell detection was 150-500 cells/wells. In cytotoxicity assays eight clinically used cytostatics were tested which effected a clear dose-response relationship (r = 0.93-0.98) and high reproducibility (r = 0.92). In conclusion, this assay is a simple and rapid test system, the main advantages are the absence of any washing steps and the small number of tumor cells necessary for drug testing. The PIA can easily be used for cell number determinations in biological and pharmacological studies.

Targeted inhibition of tumor-cell growth by recombinant heregulin-toxin fusion proteins.

Fusion of functional domains of proteins by in vitro recombination of gene fragments can be used to generate novel anti-tumor agents. The combination of tumor-cell-recognition functions and toxic functions results in cytotoxic molecules with a high specificity for tumor cells. Human adenocarcinomas are frequently characterized by over-expression of members of the epidermal-growth-factor (EGF) receptor family (ErbB-1, 2, 3 and 4), when compared with normal cells. These tumors are particularly suited to treatment with recombinant toxins. The human heregulins (HRG) and their rat counterparts (neu differentiation factor, NDF) have been identified as ligands for these receptors. Two chimeric heregulin-toxin fusions consisting of the EGF-like receptor recognition domain of the heregulin isoforms HRG alpha and HRG beta I, and the domains II, Ib and III of the Pseudomonas exotoxin A (ETA) were constructed. HRG beta I-ETA is highly cytotoxic for the mammary carcinoma cell lines SK-BR-3 and MDA-MB-453. HRG alpha-ETA was less active than HRG beta I-ETA. The killing activity of the recombinant toxins correlated with the expression levels of ErbB-3 and/or ErbB-4 in the cell lines studied. High expression of ErbB-2 is not sufficient to confer sensitivity towards the HRG-ETA. Treatment of mice with 0.4 mg/kg/day of HRG beta I-ETA caused growth retardation of transplanted human breast tumor cells. Higher levels of HRG beta I-ETA administration resulted in acute hemorrhagic necrosis of the liver.

Cycloplatam: a novel platinum compound exhibiting a different spectrum of anti-tumour activity to cisplatin.

Cycloplatam is a novel platinum compound which has shown anti-tumour activity in murine tumour models. In this study, cycloplatam was found to have anti-tumour activity in vitro and in vivo in human tumour models. In 15 cell lines (mainly ovarian), cycloplatam showed similar cytotoxicity as cisplatin, using the sulphorhodamine B assay. Determination of the resistance factor (IC50 of cisplatin-resistant divided by IC50 of parental cell line) clearly showed lower values for cycloplatam than for cisplatin. In the parental ovarian cell line CH1 and the cisplatin-resistant CH1 cisR model, we observed no cross-resistance of cycloplatam and cisplatin. The in vitro anti-tumour activity was confirmed in human tumour xenografts using the clonogenic assay. Mean IC70 values of cycloplatam were 0.54 microgram/ml (1.25 microM) and of cisplatin 0.42 microgram/ml (1.4 microM), respectively. In the murine subcutaneously implanted ADJ/PC6 plasmacytoma in vivo cycloplatam showed less activity than cisplatin, with a 2-fold smaller therapeutic index than cisplatin. In ovarian cancer xenografts cycloplatam was less active than cisplatin. However, anti-tumour activity of cycloplatam in lung cancer xenografts was quite different from cisplatin. In LXFS 538, a model moderately sensitive to cisplatin, a partial remission was observed, but in LXFL 529, a cisplatin-sensitive model, cycloplatam was inactive, cycloplatam thus demonstrating a different spectrum of anti-tumour activity. Based on these results, further preclinical investigations with other tumours, such as cisplatin-sensitive and -resistant gastric cancer models, are warranted with cycloplatam.

Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow.

Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)